A large number of studies have indicated that a diet high in vitamin A and carotenoids is protective against a variety of cancers. One of the most striking results was reported last year by Hong and co-workers who showed that the synthetic retinoid isotretinoin (13-cis retinoic acid) administered in a high dose as adjuvant therapy, reduces significantly the occurrence of second primary tumors in patients with squamous cell carcinomas of the head and neck. These second primary tumors are the major reason for treatment failure and death in patients which have undergone successful therapy of their early staged primary tumors. The mechanism underlying the cancer preventive effects of retinoids (synthetic vitamin A derivatives) is still poorly understood. A potential model was provided by the identification of retinoic acid receptors (RAR) as members of the steroid/thyroid hormone receptor superfamily. These are ligand-activated enhancer proteins which interact with cognate DNA sequences and thereby modulate transcription from adjacent promoters. A recent exciting finding in our laboratory has revealed a novel mechanism in which RARs and the cellular Jun/Fos oncogene products antagonize each other by direct protein/protein interaction. Thus, RAR in the presence of retinoids can directly interfere with the signal transduction pathway, used by many growth factors and viral and cellular oncogenes. We propose here an analysis of this new mechanism and the characterization of retinoids with optimal anti-oncogene activity and receptor specificity. Such retinoids are likely to have minimal side effects, side effects being the major problem with presently use retinoids. RAR protein domains interacting with the c-Jun/c-Fos oncoproteins will be determined using in vitro mutagenesis systems, transient transfection assays and gel retardation. CDNAS, encoding proteins that interact with RAR and c-Jun will be selected and analyzed, using a recently described approach employing biotinilated proteins as probes. The results from this research will lead to the understanding of the molecular mechanism by which nuclear receptors can interfere with oncogene activities and enable the design of potent novel retinoids with reduced side effects as therapeutics against cancers.